Cyclodextrins (CDs) are a family of cyclic oligosaccharides composed of α-(1,4) linked glucopyranose subunits. According to the general accepted nomenclature of cyclodextrins an α (alpha)-cyclodextrin is a 6-membered ring molecule, a β (beta)-cyclodextrin is a 7-membered ring molecule and a γ (gamma)-cyclodextrin is a 8-membered ring molecule. The cyclodextrins are useful molecular chelating agents. They possess a cage-like supramolecular structure. As a result of molecular complexation phenomena CDs are widely used in many industrial products, technologies and analytical methods.
Sugammadex is marketed as Bridion® and structurally known as compound of formula I. It is an octa substituted γ-cyclodextrin derivative with a lipophilic core and a hydrophilic periphery.

Sugammadex contains eight recurring amylose units each with five asymmetric carbon atoms, in total forty asymmetric carbon atoms for the whole molecule. The original configuration of all asymmetric carbon atoms is retained during the synthetic manufacturing process.
Sugammadex is known to be useful for the reversal of neuromuscular blockade induced by the steroidal neuromuscular blocking agents (NMBA) such as rocuronium, vecuronium and pipecuronium.
Sugammadex was disclosed in WO01/40316A1. This publication discloses a process for preparation of sugammadex which involves preparation of a halogenating agent by reacting triphenylphosphine, iodine and dry dimethylformamide. The halogenating agent is further reacted with dry γ-cyclodextrin of the compound of formula II at 70° C. for 24 hrs.

After reaction completion, the obtained solution is treated with sodium methoxide and methanol. The methanol is evaporated, then water is added to obtain hard viscous oil. The hard viscous oil is filtered and washed three times each with water and acetone to obtain 6-per-deoxy-6-per-iodo-γ-cyclodextrin as a yellow solid. The 6-per-deoxy-6-per-iodo-γ-cyclodextrin is reacted with 3-mercaptopropionic acid in the presence of sodium hydride in dry dimethylformamide to obtain sugammadex.
The process disclosed in WO01/40316A1 suffers from the following disadvantages:                (i) The preparation of a halogenating agent produces triphenylphosphine oxide as by product, which is very difficult to remove from the reaction mass. Normally it requires multiple washing with a solvent under inert atmosphere for complete removal.        (ii) The addition of sodium methoxide to the dimethylformamide solution is very exothermic and difficult to control.        (iii) The reaction mixture is very viscous after removal of methanol and cumbersome to stir.        (iv) The filtration of hard viscous oil is very slow which makes solvent washing very difficult and time consuming.        (v) The obtained yield of 6-per-deoxy-6-per-iodo-γ-cyclodextrin is very low (about 40%).        (vi) The purity of 6-per-deoxy-6-per-iodo-γ-cyclodextrin is also very low (about 20%).        (vii) The use of sodium hydride is also very challenging as it is associated with extensive foaming, formation of explosive hydrogen gas, and the addition of mineral oil to the reaction mixture.        
WO2012/025937A1 discloses the preparation of sugammadex by chlorination of γ-cyclodextrin with a halogenating agent prepared from phosphorous pentachloride and dimethylformamide. After completion of the chlorination the solvent is removed to obtain a viscous residue. The viscous residue is diluted with water followed by adjusting the pH 8 with 5M sodium hydroxide to obtain a slurry. Said slurry is then filtered, washed with water and dried to give 6-per-deoxy-6-per-chloro-γ-cyclodextrin. The chlorinated γ-cyclodextrin is further reacted with 3-mercaptopropionic acid in the presence of sodium hydride in dimethylformamide to give sugammadex. This publication also discloses that the prepared halogenation agent reacts selectively with primary hydroxyl groups of γ-cyclodextrin to provide 6-per-deoxy-6-per-chloro-γ-cyclodextrin.
The process disclosed in WO2012/025937A1 suffers from the following disadvantages:                (i) The halogenating agent, which is prepared by reaction of phosphorous pentachloride and dimethylformamide, produces numerous phosphorous species on reaction with dimethylformamide, and its subsequent use for the halogenation of γ-cyclodextrin also produces phosphate esters as impurities which are difficult to remove.        (ii) The removal of dimethylformamide after chlorination of γ-cyclodextrin gives highly viscous oil, which is very cumbersome to stir.        (iii) The addition of water to the obtained viscous oil is highly exothermic and handling of such exothermic reaction is very difficult.        (iv) The filtration of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is also very challenging due to its amorphous nature and it takes very long time for the filtration.        (v) The obtained yield of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is very low (about 44%).        (vi) The purity of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is also very low (about 22%).        
WO2014/125501A1 discloses the preparation of sugammadex by chlorination of γ-cyclodextrin with a halogenating agent, prepared from phosphorous pentachloride and dimethylformamide. After completion of the chlorination, the mixture is quenched with water. The obtained mixture is hydrolyzed with aqueous sodium hydroxide solution, filtered, washed repeatedly with water and dried to give 6-per-deoxy-6-per-chloro-γ-cyclodextrin. The chlorinated γ-cyclodextrin is further reacted with 3-mercaptopropionic acid in presence of sodium methoxide in dimethylformamide to give crude sugammadex. The crude sugammadex is purified by treating with activated carbon in a mixture of water and methanol.
The process disclosed in WO2014/125501A1 suffers from the following disadvantages:                (i) The halogenating agent, which is prepared by reaction of phosphorous pentachloride and dimethylformamide, produces numerous phosphorous species on reaction with dimethylformamide, and its subsequent use for the halogenation of γ-cyclodextrin also produces phosphate esters as impurities which are difficult to remove.        (ii) The filtration of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is very challenging as it takes very long time for the filtration due to its amorphous nature.        (iii) The purity of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is also very low (about 23%).        
Thus, the prior art procedures for the preparation of sugammadex suffer from the following disadvantages outlined below;                (i) The use of triphenylphosphine during the iodination of γ-cyclodextrin, the use of phosphorus based reagents for the halogenation of γ-cyclodextrin. These reagents produce unwanted impurities as by product which is very difficult to remove and require multiple purifications.        (ii) The handling of highly viscous reaction mixture of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is very difficult.        (iii) The filtration of 6-per-deoxy-6-per-chloro-γ-cyclodextrin is also very challenging due to its amorphous nature.        
Finally, the longer time duration, handling of reaction and multiple purifications for the removal of impurities are not desirable for the preparation of sugammadex and its intermediates.